特比萘芬的合成

0D 1000iE°6NsNs+"8Journal of China Pharmaceutical University 2001 ,32(1):8~9i0+EYA -O0μA≌T3∈2u 0"*, |>EWe+，1AE=xi(0D10@iE "6NgO@Y> "NgyhINDEO, A1T34G 210009)0日 0日 AiuA:NDWEi0aWwuOOi0EYA -0μA*°3EA- IBW°01=00。 -k- :00EμAA ji EeE/4O-AT,4- AE u, INAE* Ca,。nET-*0!μA6,6- 1p/x>-1-。y10-4- E2-3-“%4(5),a °u260e N -4x>0-1- YAV4x0..' 0: μAte ia>-eTr。怕10: EAEAie》-9T个,Ea6a114- IR,HNMR ,MS , 0∞∈0.01oμA00E-0y。%aA0 : e[3EA- T1BV° 100%TEE0A001a0μ>~Eu2u。10W0E I&GOeTO>.No>-A. ,0EVA; 10EYA-0; ,nE1--0|; °300 [% -0AaRA:R978.5;R914.5TA1xteEqAe:A 1A0AtaA: 1000- 5048<2001)01 0008- 02i0E YA -0(terbinafine ) ECδ∞WwuWCe 10》. NO>- 0|μAAiteT。 a0D 4 0et0TOE@40≥∈.0! ,μ1A16/4pA. 100i 0000OEVA, 6A0U0T AEC3+1E -60∞%2i, εE0O0@C6. ,B(-70C)。T0Ac2i i%qμUp16A- IB ,00EμAA自1ryi0 +>>0%02i .o00。AEDSRA,0TAE, -cAEμi ,9%土↑βEE40- AT ,%-AE U、NAE>- Ca ,0FμA4。OUOE3∈E2x+ 0AD[1。TAIx+"~ μA i0坨YA _0μA°3∈A- TBOBAV。nETEOMA96, u iaOy9i >U0e tQT@EO-' 0| , 1-Nu0F152]。0> 16EG0E N-/4x >0-1- YAl4x°.eiEa9i >ui IpμA 5, 91o.-01 )b'DetuNTOjAaE" (一10C)。Af la0B%aE2、9a4U14x E@OUAE>- NC1- "B》TAOFμA N- (6, 6- 9Ip%4xla 4 μAOEt, , 60%0Ee Iax 0E B》ViAEAOyTi >UT890，>0-2,4- ,yY仆E2 >U)-N-%4x>u- 1- YA1x°. ,0U0A 5 t1AiE1ATx 2UAEC3OE 70%ia. BOA 90%00EY。D/ala N-μA Ip0i 9i >uCaAA(DIBAL)>10- iEμAAite1r。. AA. N4x>u- 1- YAIx°.uAO0F土。。1ATx -*"04E40200 50% xoB0ED/4alaOE土。AgAN, Eu0A0- AT3E+$%2T B, 10μ>~Eu 00, 2c0DIaμ+AjμA N- E《1e>u>- 2个TEu3E,"1y Ata2uAsAN。A1O> 16A- IBECOOEaqi >u00E2(4)T@0-AT,00 E0O%A91O06N0%x°_OAAε ,E0TA-01%4" εμAμh2° iq作%Y ,Boy1i >@ a0U1A0e+0T0E@%O≈∈EμA 6,6- }%4x》)0-5Y5 μA2o1T , 2uAE02ia. BOA 76% , 1yAi I4x "W4eE00>0E01x10-4- E2-3- *%4(5),Eaaa u960e N-4x>i- 1 _YANx°..0A。9[3EA-IBEqTA:(CHs):CCCHg ' 一(CH3);C C CH3 .KOH/DMSO. (CH)CC=CH1DN/E0.CH.CHzBr. (CH),CC=C CH CH-CHPBr3PTC2)CH2 = CHCHOHBrNH、CH2H. HCI(CH3)2C C=C CH=CHmmCH2Br+Eaqi >uC0E2(4)EμNe2i -016eu PCl; 37. 5 g(0.18 mol )0A0UEy%土压j0D , tu0iEQμa0U wC- 1 D1T01φEOμa0CET2aq" , TAnEX&ETAaE°TAμ1%OEμAAi≌18. 0 g(O. 18 mol), y40+141 DoWA%4- DfOy ;9i la1aEx0C1日Perkin Elmer 983D1,1i1a咱9h。E> 96CaEe 100 g Ee tu0D , 0U%4OEeOOANEU/aDUa》>~V40N1 AE-;0≈E0 -0160C1a Carol Erba 1106Di;9E。iμA1iia, -δ38AN2a, E:2a0AOOAN-"。”iaEi , 9[2cANA120nCaEx 2E0A Bruker ACF -300 D[zag", TMS 2a,1" 0AGDDO.. ,E0r960δ3y0AN , μuAIpAE uT(3)°0个@AUe ;0Ex 2ar0C@ Nicolet FTMS- 2000D1,EI- AE- 1中国煤化工.2[ 2 +TAqμA KOH O>70 eV ;TLC 0A1e/6e GFz3x00Eti a,μa。xTOE<。i-EMHC N M H GWOEeEAOyTi >UTS 1. 0g,yA°e IA>9 AyEyTA, EO%- -Dμa 40 C 00TAμA636T,E0_ aE0EU 2000- 08-31”i"Nqx+OB Tel:025- 32714491 EU口u 0"μE: i0EYA -0μA°3∈uA 0E- 9. 0g。0U%- T-E10u -0AoμA 48. 60 g(90%)。NTEa(E)-N-(6,6- 1%/*x>-2- .yT0-4 E2>)-N-/%x>u>bp37~39C [TATx bp36. 4~37.8C]-1- YA14x°.(1)6,6- 9)%4x>-1- ,y10-4- E2 3- "%(5)Ey%士EiODOA TyOEe 73. 23 g(0. 0157 mol), ip/ku A%D/4 1. 32 g(0. 055 mol)91P60OAN 10 ml .国Na2CO3 6. 32 g(0. 0596 mol),6 3. 00 g(0. 01490A 60 EOπ∈Eyψ士Ei 的D,μ%000le 6. 00 g(0. 055mol) ,20 ml DMF , E0TAvAe 1y01。YAoN1063y DMF，mol )40 DPE@0AN 10 ml μA>i2T0° , EUAjuaoy -c-0:2D0u0AE@E}始6 , OAOOANqa个YIE; , [2cAN2a,0A个20,4100A+ 2 h。tu0jAaE' TAμ1404 4. 1 g(0. 050A甸、2%%4E白、朗、￥9「NaHCO3、E@Yμ0, Dp蛔mol )001PE@00AN 5 ml μAE00° , y40tT%A°e 1y01。0U0Na2SO.. E0r, i" EeAE>~CaEo 1a0At￥9 i ,003y0ANμANTOjAaE" 1A(- 10C),0UTWOt0TOE@ 3.08 g(0. 055x>>E<01x个r。0A9-ODEUAjAE 》~ CaμA0i +0“V%- 00ANmol )0U1PE800AN 5 ml μAE00O , 40+TEOTAyi DoWAe(1 : 4 v/v)00YawsμA°xE<%S la1 1. 80 g(43%)。mp6 h,E> °6>2AyμT40 15% H2SO, 30 ml。-038AN2a,196~ 199C[1ATx mp 195~ 196C]。IR ( KBr,民zaOA00ANIaEi , 92cAN2a,Tu0, ,Eσr。063y0OAN .cmi -1 )v 3400, 3040, 3010, 2400, 1630, 1 600, 1500, .6 , Y46N1 08A6EOv7 bp42~ 43 C (399.9Pa)Ao -0,uA1475, 1400, 960, 800, 770; HNMR (CDCl3),88. 15 2.20 g(32%)[TAIx bp 73~75C(1 599. 6Pa)]。~ 7. 53(m, 7H,Ar H),6. 36(dm, 1H,J= 15Hz,1- a-6,6- 1b)%x>1-2-. ,yT0-4 E2(6)(E)- CH=CH), nb5.88 (dm,1H,J= 15Hz,(E)-.EOrEy%4+EjOD)4Ee HBr(48%)7. 5 ml , oUμTEeCH =CH), 4.69 (dm, 2H, ArCH2N), 3.77 (dm，PBr3 0.52 ml，yzA°e0A4u0>。tu0jAaE 1Aμ1%05 2.112H, NCH2CH= ),2.64(d, 3H,NCH3), l.24(s,g(0. 015 mol)0U1pE@00“14 25 ml μAE00e , 4OHTEOTA9H, t- Bu), 12.65(br, 1H,NH+ );MS(m/z)291;y1DohAoe,0A TLC。uxU0A-*0:ieE<。.0|0°Ga0A Anal. C2H2;N●HCI %C、H、N -0t01 76. 92,7.50g tu0D , 0A》.1%2 ie 50 ml -0个Y1Ei , 9[2cYIEi99,4.27(ATAU0μ 76. 92,7. 98,4. 65)。0,1-0A0DD0,，E0T96/46N1 >OEOEO%A,μA OE- 63. 002i iW 1A1xg(E/Z=3: 1)。2>%- -0Ae0ty6OYko明N- ie >吣》.'[1] Stutz A. Allylamine derivatives-a new class of active sub-stances in antifungal chemotherapy[J]. Angew Chem Int EdN4x>i- 1- YAV4x° .NTEaNT (7)Engl,1987 .26(4):320- 328.《1-AE%4x >uYA 8. 83 g(0. 05 mol)[1PE@00 "14[2] Stutz A.Petranyi G. Synthesis and antifungal activity of SF-86- 327 and related allylamine derivatives with enhanced oral15 ml uA>i °T0° ,VAe TAμTEe9-0D 22 g(0. 7 mol)%xactivity[J]. J Med Chem,1984.27(12):1539.°.μA "W4EU00D , EOTANA°e 36 h。>OEO0%x 。. °4E009,[3] Sowa JR ,Gordinier A,Lamby EJ, et al. Tert -Butyacetylene2E0u0A 30 ml AE -AEUae6, I 0AODDO,. E0T96 i"Ee .[J]. Organic Synthesis, 1973,53:1830.[4] Hutton RC，Salam SA. Stephen WI. Organic reagents for theAE>- ca0At$2[ ,46N1 063yAE -A, -OE-0A TPE@0O 1400precipitation of nitrate iNO. Part I N-substituted 1- naph-V%aNsμA2o1T 77. 90 g(76%)。mp182~184 c[TATxthyl- methylamine[J]. J Chem Soe, 1966, A(11): 1573-mp190C(0i t0“"4)]1579.Synthesis of TerbinafineHAN Ying, HUANG Jia-Zi, TU Shu-ZiDepartment of Medicinal Chemistry ,China Pharmaceutical University, Nanjing 210009Abstract AIM: To develop a modification of the general中国煤化工terbinafine. METH-ODS: Compound (1) was synthesized from 1 -bromo- 6, 6:MYHC N M H G(6) by reaction withN-methyl-1-naphthalenemethanamine. Compound 5 was prepared from tert-butylacetylene(4) throughGrignard reaction with acrolein. R ESULTS: The title compound was synthesized. The structure wasconfirmed by IR，HNMR, MS and elemental analysis data. CONCLUSION: Some improvements for thesynthesis对方数据unds 4,5 and 7 were made.Key words squalene expoxidase inhibitor; terbinafine; grignard reaction; synthesis